Many disease processes cause profound changes in the mechanical properties of tissue, providing motivation for developing technologies to measure these properties for diagnostic purposes. In addition, over the last decade there has been growing awareness of the importance of tissue matrix mechanics on cellular function. Cells react to the dynamic and static properties of their matrix environment through mechanotransduction and cytoskeletal remodeling. It is now known that mechanobiology has an important role in the origin and evolution of many disease processes, including fibrosis and cancer. The goal of this research is to develop advanced MRI-based technologies for quantitatively assessing the mechanical properties of tissue and to explore and translate high-impact clinical and research applications. MR Elastography (MRE) is based on the principle that propagating mechanical waves reflect the properties of their medium. Shear waves are generated in the body and imaged with MRI techniques that have the remarkable ability to depict cyclic motions as small as 100 nanometers. The data are processed with inversion algorithms to provide cross-sectional images quantitatively depicting mechanical properties such as the complex shear modulus. In the last grant cycle, the hepatic MRE technology developed under this grant was successfully translated into wide clinical practice and is now used in patient care at hundreds of medical facilities around the world. Liver fibrosis is an important health problem with a rising prevalence in the US population. For many patients, MRE provides a safer, more comfortable, and less expensive alternative to liver biopsy for diagnosing this condition. Research has revealed many other promising applications, including noninvasive diagnosis of fibrosis and inflammation in other organs, detection and characterization of malignancies, providing new biomarkers to assess brain disease, and as a tool in basic research mechanobiology at the tissue and organ scales. As in the last grant cycle, the primary focus of the work will continue to be advanced technology development, to enable further basic and clinical research in this promising field, as well as to conduct pilot studies to identify clincal applications, and to develop practical protocols that will allow validation and eventual translatio to MRE to clinical practice. The research plan involves theoretical work, basic MRI pulse sequence development, device engineering, and protocol testing studies with normal and patient volunteers. Innovative approaches will be implemented and evaluated for generating mechanical waves in tissue, acquiring image data, and processing to generate quantitative images depicting previously inaccessible biomarkers. These technologies will be integrated into protocols that can be shared with other investigators and used to explore the practicality and value of promising applications.